Mendzelevski Boaz, Sprenger Craig R, Spiegelstein Ofer, Rabinovich-Guilatt Laura
Int J Clin Pharmacol Ther. 2014 Mar;52(3):192-201. doi: 10.5414/CP201955.
Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor, developed for the treatment of Parkinson's disease. In compliance with current regulatory requirements, rasagiline underwent a thorough QT/QTc (TQT) study to assess its potential to prolong cardiac repolarization. The primary aim of this study was to evaluate the effects of clinical (1 mg/day) and supratherapeutic (2 mg/day and 6 mg/day) multiple oral doses of rasagiline on the baseline- and placebo-adjusted QTc interval (delta delta QTc (ddQTc)). Other electrocardiogram parameters, pharmacokinetic assessments, safety and tolerability as well as vital signs were investigated.
This was a five-arm, randomized, double-blind, placebo- and active-controlled, and parallel study in healthy subjects. Moxifloxacin (400 mg) positive control was included to demonstrate assay sensitivity.
247 of 250 randomized subjects completed the study. Time-matched analysis of ddQTc yielded two-sided 90% confidence intervals for all rasagiline doses below the 10 ms regulatory threshold, showing no effect on cardiac repolarization. Concentration-effect analysis demonstrated no relationships between rasagiline (and its metabolite 1-aminoindan), plasma concentrations, and ddQTc. The pharmacokinetic profile of rasagiline was consistent with previous studies. Adverse events were mild to moderate in intensity and were similar across all treatment groups. There were no clinically significant changes in heart rate and systolic blood pressure.
This TQT study demonstrated a favorable cardiac safety profile of rasagiline.
雷沙吉兰是一种选择性、不可逆的单胺氧化酶B型抑制剂，用于治疗帕金森病。按照当前监管要求，雷沙吉兰进行了一项全面的QT/QTc（TQT）研究，以评估其延长心脏复极化的可能性。本研究的主要目的是评估临床剂量（1毫克/天）和超治疗剂量（2毫克/天和6毫克/天）的雷沙吉兰多次口服给药对基线和安慰剂校正后的QTc间期（△△QTc，即ddQTc）的影响。还对其他心电图参数、药代动力学评估、安全性和耐受性以及生命体征进行了研究。
这是一项在健康受试者中进行的五组、随机、双盲、安慰剂和活性对照的平行研究。纳入莫西沙星（400毫克）阳性对照以证明检测灵敏度。
250名随机分组的受试者中有247名完成了研究。对ddQTc进行时间匹配分析得出，所有低于10毫秒监管阈值的雷沙吉兰剂量的双侧90%置信区间显示，对心脏复极化无影响。浓度-效应分析表明，雷沙吉兰（及其代谢物1-氨基茚满）、血浆浓度与ddQTc之间无相关性。雷沙吉兰的药代动力学特征与先前研究一致。不良事件强度为轻度至中度，所有治疗组相似。心率和收缩压无临床显著变化。
这项TQT研究表明雷沙吉兰具有良好的心脏安全性。
